Synthesis of new benzothiazole derivatives as potential anti-tubercular agents

ABSTRACT

The present disclosure provides compounds of general formula A: 
                         
useful as potential anti-tubercular agents.

BACKGROUND

1. Field of the Disclosure

The present disclosure relates to benzothiazole compounds asanti-tubercular chemotherapeutic agents and the process for thepreparation thereof. Particularly, the present disclosure relates to2,6-substituted benzothiazole compounds of general “formula A”.

-   X=—N═CH—, —NH—CO—, —CO—-   Ar=Phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,    4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,    2-chloro-3-methoxyphenyl, 3,5-dimethoxyphenyl,    3,4,5-trimethoxyphenyl, pyridyl, nicotenyl, isonicotinyl,    5-nitro-2-furyl, styryl, 4-fluorostyryl, 4-methylstyryl,    4-methoxystyryl, 4-trifluorostyryl, 4-trifluoromethoxystyryl,    5-nitro-2-furyl, 1-methyl-4-nitro-1H-2-pyrrolyl,    1-methyl-5-nitro-1H-2-imadazolyl, 1-methyl-3-nitro-1H-2-pyrazolyl-   R=Hydro, Methyl, Methoxy, Trifluoromethyl, Trifluoromethoxy, Fluoro,    Chloro, Nitro, 5-Nitrofuran-2-carboxamide,    5-Nitrothiophene-2-carboxamide,    1-methyl-4-nitro-1H-2-pyrrolcarboxamide,    1-methyl-5-nitro-1H-2-imadazolcarboxamide,    1-methyl-3-nitro-1H-2-pyrazolcarboxamide

The structural formula of these benzothiazole compounds is given belowand is represented by the following compounds of formula 3a-p, 4a-h,6a-w and 8a-d.

-   R=H, CH₃, OCH₃, CF₃, OCF₃, F, Cl, NO₂-   X=O, S

-   R=H, CH₃, OCH₃, CF₃, OCF₃, F, Cl, NO₂

-   Ar=Phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,    4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,    2-chloro-3-methoxyphenyl, 3,5-dimethoxyphenyl,    3,4,5-trimethoxyphenyl, pyridyl, nicotenyl, isonicotinyl,    5-nitro-2-furyl, styryl, 4-fluorostyryl, 4-methylstyryl,    4-methoxystyryl, 4-trifluorostyryl, 4-trifluoromethoxystyryl

-   Ar=5-nitro-2-furyl, 1-methyl-4-nitro-1H-2-pyrrolyl,    1-methyl-5-nitro-1H-2-imadazolyl, 1-methyl-3-nitro-1H-2-pyrazolyl

2. Discussion of the Background Art

As a part of investigation of new chemotherapeutic agents from thislaboratory, over the past eight years our research efforts have beenfocused towards the intervention of new scaffolds with goodantimycobacterial activity and eventually to develop new anti-tubercularagents that can improve the current therapeutic regimen as well aseffective in the treatment of MDR-TB (Kamal, A.; Babu, A. H.; Ramana, A.V.; Sinha, R.; Yadav, J. S.; Arora, S. K. Bioorg. Med. Chem. Lett. 2005,15, 1923-1926; Kamal, A.; Reddy, K. S.; Ahmed, S. K.; Khan, M. N. A.;Sinha, R. K.; Yadav, J. S.; Arora, S. K. Bioorg. Med. Chem. 2006, 14,650-658; Kamal, A.; Ahmed, S. K.; Reddy, K. S.; Khan, M. N. A.; Shetti,R. V. C. R. N. C.; Siddhardha, B.; Murthy, U. S. N.; Khan, I. A.; Kumar,M.; Sharma, S.; Ram, A. B. Bioorg. Med. Chem. Lett. 2007, 17,5419-5422).

In early 80s, diverse biological properties have been reported onbenzothiazole scaffold including anti-tubercular activity by differentresearch groups around the globe. (Palmer, P. J.; Trigg, R. B.;Warrington, J. V. J. Med. Chem. 1971, 14, 248; Katz. L.; J. Med. Chem.1953, 75, 712; Palmer, P. J.; Ward, R. J.; Miyamastu, H.; Uneo, H.;Shimizu, H.; Hosono, J.; Tomari, M.; Seida, K.; Suzuki, T.; Wada, J. J.Med. Chem. 1974, 17, 491; Shi, D-. F.; Bradshaw, T. D.; Chua, M-. S.;Westwell, A. D.; Stevens M. F. G. Bioorg. Med. Chem. Lett. 2001, 11,1093.

Klimesova and co-workers have developed the bezylsulfanyl moiety at C-2position of benzothiazole with good antimycobacterial activity. Further,Schiff bases and hydrazones of benzothiazoles are also found to beactive against Mycobacterium tuberculosis (Koci, J.; Klimesova, V.;Waisser, K.; Kaustova, J.; Dahsec, H.-M.; Mollmannc, U. Bioor. Med.Chem. Lett. 2002, 12, 3275; Katz. L.; J. Am. Chem. Soc. 1953, 75, 712).Recently Kozikowski and co-workers have developed the 2-methyl-5-amidobenzothiazoles as potential anti-tubercular agents (Huang, Q.; Mao, J.;Wan, B.; Wang, Y.; Brim, R.; Franzblau, S. G.; Kozikowski, A. P.; J.Med. Chem. 2009, 52, 6757). These molecules are believed to inhibit theHisG enzyme of Mycobacterium tuberculosis (Cho, Y.; Ioerger, T. R.;Sacchettini, J. C. J. Med. Chem. 2008, 51, 5984). In additionnitrobenzothiazole amides have shown interesting anti-tubercularactivity, by binding to HisG enzyme of M. tb (de Carvalho, L. P. S.;Lin, G.; Jiang, X.; Nathan, C. J. Med. Chem. 2009, 52, 5789; Dykhuizen,E. C.; May, J. F.; Tongpenyai, A.; Kiessling, L. L. J. Am. Chem. Soc.2008, 130, 6706).

On the other hand, nitrofuran is an important scaffold in many potentialanti-tubercular agents Lee, R. E., Tangapally, R. P., Yendapally, R.,McNeil, M., Lenaerts, A. US 2005/0222408 A1; Tangallapally, R. P.,Yendapally, R., Lee, R. E., Lenaerts, A. J. M., Lee, R. E., J. Med.Chem. 2005, 48, 8261.

Similarly, 5-nitrothiophene key intermediate in many activeanti-tuberculosis compounds (Rando, D. G.; Sato, D. N.; Siqerira, L.;Malvezzi, A.; Leite, C. Q. F.; Amaral, A. T.; Ferreiraa, E. I.;Tavaresa, L. C.; Bioorg. Med. Chem. 2002, 10, 557; Murugasu-Oei, B.;Dick, T. J. Antimicrob. Chemother. 2000, 46, 917). These findings haveencouraged us for the design and synthesis of newnitrofuran/nitrothiophene conjugated benzothiazoles and subsequentlyevaluated for activity against tubercular cultures.

The main object of the disclosure is to provide the new benzothiazolecompounds as useful anti-tubercular chemotherapeutics.

Another object of the present disclosure is to provide a process for thesynthesis of these new benzothiazole compounds as usefulchemotherapeutic agent against sensitive and MDR-strains of TB.

Another object of the present disclosure is to provide a new mechanisticanti-tubercular agents against sensitive and MDR strains of tuberclebacilli.

Another object of the present disclosure is to provide new compoundsbased on the benzothiazole scaffold in good yields.

SUMMARY OF THE DISCLOSURE

Accordingly, the present disclosure provides benzothiazole compounds asanti-tubercular chemotherapeutic agents and the process for thepreparation thereof.

In one embodiment of the present disclosure, benzothiazole compounds ofgeneral formulae A

-   X=—N═CH—, —NH—CO—, —CO—-   Ar=Phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,    4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,    2-chloro-3-methoxyphenyl, 3,5-dimethoxyphenyl,    3,4,5-trimethoxyphenyl, pyridyl, nicotenyl, isonicotinyl,    5-nitro-2-furyl, styryl, 4-fluorostyryl, 4-methylstyryl,    4-methoxystyryl, 4-trifluorostyryl, 4-trifluoromethoxystyryl,    5-nitro-2-furyl, 1-methyl-4-nitro-1H-2-pyrrolyl,    1-methyl-5-nitro-1H-2-imadazolyl, 1-methyl-3-nitro-1H-2-pyrazolyl-   R=Hydro, Methyl, Methoxy, Trifluoromethyl, Trifluoromethoxy, Fluoro,    Chloro, Nitro, 5-Nitrofuran-2-carboxamide,    5-Nitrothiophene-2-carboxamide,    1-methyl-4-nitro-1H-2-pyrrolcarboxamide,    1-methyl-5-nitro-1H-2-imadazolcarboxamide,    1-methyl-3-nitro-1H-2-pyrazolcarboxamide

In another embodiment of the present disclosure, benzothiazole compoundsof general formulae is represented by the compounds of general formula3a-p, 4a-h, 6a-w and 8a-d.

-   R=H, CH₃, OCH₃, CF₃, OCF₃, F, Cl, NO₂-   X=O, S

-   R=H, CH₃, OCH₃, CF₃, OCF₃, F, Cl, NO₂

-   Ar=Phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,    4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,    2-chloro-3-methoxyphenyl, 3,5-dimethoxyphenyl,    3,4,5-trimethoxyphenyl, pyridyl, nicotenyl, isonicotinyl,    5-nitro-2-furyl, styryl, 4-fluorostyryl, 4-methylstyryl,    4-methoxystyryl, 4-trifluorostyryl, 4-trifluoromethoxystyryl

-   Ar=5-nitro-2-furyl, 1-methyl-4-nitro-1H-2-pyrrolyl,    1-methyl-5-nitro-1H-2-imadazolyl, 1-methyl-3-nitro-1H-2-pyrazolyl-   In another embodiment of the present disclosure, benzothiazole    compounds of general formula A, wherein    the structural formula of the representative compounds are:-   3a). 5-nitro-2-furaldehyde 2-(1,3-benzothiazole-2-yl)hydrazone;-   3b). 5-nitro-2-thiophenecarbaldehyde    2-(1,3-benzothiazole-2-yl)hydrazone;-   3c). 5-nitro-2-furaldehyde    2-(6-methyl-1,3-benzothiazole-2-yl)hydrazone;-   3d). 5-nitro-2-thiophenecarbaldehyde    2-(6-methyl-1,3-benzothiazole-2-yl)hydrazone;-   3e). 5-nitro-2-furaldehyde 2-(6-methoxy-1,3-benzothiazole-2-yl)    hydrazone;-   3f). 5-nitro-2-thiophenecarbaldehyde    2-(6-methoxy-1,3-benzothiazole-2-yl)hydrazone;-   3g). 5-nitro-2-furaldehyde    2-(6-trifluoromethyl-1,3-benzothiazole-2-yl)hydrazone;-   3h). 5-nitro-2-thiophenecarbaldehyde    2-(6-trifluoromethyl-1,3-benzothiazole-2-yl)hydrazone;-   3i). 5-nitro-2-furaldehyde    2-(6-trifluoromethoxy-1,3-benzothiazole-2-yl)hydrazone;-   3j). 5-nitro-2-thiophenecarbaldehyde    2-(6-trifluoromethoxy-1,3-benzothiazole-2-yl)hydrazone;-   3k). 5-nitro-2-furaldehyde    2-(6-fluoro-1,3-benzothiazole-2-yl)hydrazone;-   3l). 5-nitro-2-thiophenecarbaldehyde    2-(6-fluoro-1,3-benzothiazole-2-yl)hydrazone;-   3m). 5-nitro-2-furaldehyde    2-(6-chloro-1,3-benzothiazole-2-yl)hydrazone;-   3n). 5-nitro-2-thiophenecarbaldehyde    2-(6-chloro-1,3-benzothiazole-2-yl)hydrazone;-   3o). 5-nitro-2-furaldehyde    2-(6-nitro-1,3-benzothiazole-2-yl)hydrazone;-   3p). 5-nitro-2-thiophenecarbaldehyde    2-(6-nitro-1,3-benzothiazole-2-yl)hydrazone;-   4a). N′2-(1,3-benzothiazol-2-yl)-5-nitro-2-furancarbohydrazide;-   4b).    N′2-(6-methyl-1,3-benzothiazol-2-yl)-5-nitro-2-furancarbohydrazide;-   4c).    N′2-(6-methoxy-1,3-benzothiazol-2-yl)-5-nitro-2-furancarbohydrazide;-   4d).    N′2-(6-trifluoromethyl-1,3-benzothiazol-2-yl)-5-nitro-2-furancarbohydrazide;-   4e).    N′2-(6-trifluoromethoxy-1,3-benzothiazol-2-yl)-5-nitro-2-furanecarbohydrazide;-   4f).    N′2-(6-fluoro-1,3-benzothiazol-2-yl)-5-nitro-2-furanecarbohydrazide;-   4g).    N′2-(6-chloro-1,3-benzothiazol-2-yl)-5-nitro-2-furanecarbohydrazide;-   4h).    N′2-(6-nitro-1,3-benzothiazol-2-yl)-5-nitro-2-furanecarbohydrazide;-   6a). N2-[2-(benzoylamino)-1,3-benzothiazol-6-yl]-5-nitrofuramide;-   6b).    N2-{2-[(4-methylbenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6c).    N2-{2-[(4-methoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6d).    N2-{2-[(4-trifluoromethylbenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6e).    N2-{2-[(4-trifluoromethoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6f).    N2-{2-[(4-fluorobenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6g).    N2-{2-[(4-chlorobenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6h).    N2-{2-[(2-chloro-3-methoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6i).    N2-{2-[(2,4-difluorobenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6j).    N2-{2-[(2,4-dichlorobenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6k).    N2-{2-[(3,5-dimethoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6l).    N2-{2-[(3,4,5-trimethoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;-   6m).    N5-(6-{[5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-2-yl)-1,3-benzodioxole-5-carboxamide;-   6n).    N4-(6-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-2-yl)isonicotinamide;-   6o).    N3-(6-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-2-yl)nicotinamide;-   6p).    N2-(6-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-2-yl)-2-pyrazinecarboxamide;-   6q).    N2-(2-{[(E)-3-phenyl-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;-   6r).    N2-(2-{[(E)-3-(4-methylphenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;-   6s).    N2-(2-{[(E)-3-(4-methoxyphenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;-   6t).    N2-(2-{[(E)-3-(4-trifluoromethylphenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;-   6u).    N2-(2-{[(E)-3-(4-trifluoromethoxyphenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;-   6v).    N2-(2-{[(E)-3-(4-fluorophenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl)-5-nitro-2-furamide;-   6w).    N2-(2-{[(E)-3-(4-chlorophenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl)-5-nitro-2-furamide;-   8a).    N2-(2-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;-   8b).    N2-(2-{[(1-methyl-4-nitro-1H-2-pyrrolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-4-nitro-1H-2-pyrrolcarboxamide;-   8c).    N2-(2-{[(1-methyl-5-nitro-1H-2-imadazolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-5-nitro-1H-2-imadazolecarboxamide;-   8d).    N2-(2-{[(1-methyl-3-nitro-1H-2-pyrazolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-3-nitro-1H-2-pyrazolecarboxamide;

In another embodiment of the present disclosure, benzothiazole compoundsof general formula A are useful as anti-tubercular agents.

In another embodiment of the present disclosure, benzothiazole compoundsof general formula A for the treatment of tuberculosis wherein therepresentative compounds 3a-p, 4a-h, 6a, 6f, 6g, 6i, 6o, 6p, 6q, 6w, 8ashowed in vitro activity against M. tuberculosis H₃₇RV in a MIC range of16 μg/mL-0.5 μg/mL.

In another embodiment of the present disclosure, benzothiazole compoundsof general formula A for the treatment of tuberculosis wherein therepresentative compound 3j, 4e, 6a, 6f, 6g, 6i, 6o, 6p, 6q, 6w showed nocytotoxicity on being tested on AML-12 cell lines.

In another embodiment of the present disclosure, a pharmaceuticalcomposition comprising a compound selected from the group of generalformula A and a pharmaceutically acceptable carrier.

In another embodiment of the present disclosure, a method for treating amycobacterial infection wherein said method comprises administering acomposition to a patient in need thereof.

In another embodiment of the present disclosure, a process for thepreparation of benzothiazole compounds of general formula 3a-p and 4a-h,wherein the said process comprises the steps of:

-   i) dissolving substituted aldehydes or 5-nitro-2-furancarboxylic    acid chloride and 2-hydrazeno-benzothiazoles in mol ratio ranging    between 1:1 to 1:1.5 in a solvent to obtain reaction mixture a or    reaction mixture b respectively;-   ii) adding acetic acid into the reaction mixture a as obtained in    step (i) followed by stirring at temperature ranges between 65° C.    to 75° C. for 2-3 hrs to obtain compounds of 3a-p;-   iii) treating reaction mixture b as obtained in step (i) with    triethylamine and N,N dimethylaminopyridine followed by stirring at    temperature ranges between 0° C.-30° C. for 12-14 hrs to obtain    compounds of 4a-h.

In another embodiment of the present disclosure, a process whereinsubstituted aldehyde used in step (i) is selected from the groupconsisting of 5-nitro-2-furancarboxaldehyde,5-nitro-2-thiophencarboxaldehyde, 5-nitro-2-nitrothiophencarboxaldehyde, 5-nitrofuran aldehyde and 5-nitrothiophen aldehyde.

In another embodiment of the present disclosure, a process wherein2-hydrazeno-benzothiazoles used in step (i) is selected from the groupconsisting of 2-hydrazino-6-methyl-benzothiazoles,2-hydrazino-6-methoxy-benzothiazoles,2-hydrazino-6-trifluoromethyl-benzothiazole,2-hydrazino-6-trifluoromethyl-benzothiazole,2-hydrazino-6-trifluoromethoxy-benzothiazole,2-hydrazino-6-fluoro-benzothiazole, 2-hydrazino-6-chloro-benzothiazole,2-hydrazino-6-nitro-benzothiazole and2-hydrazino-6-chloromethoxybenzothiazole.

In another embodiment of the present disclosure a process whereinsolvent used in step (i) is selected from the group consisting ofethanol and dry DMF.

In another embodiment of the present disclosure, a process for thepreparation of benzothiazole compounds of general formula 6a-w and 8a-d,wherein the said process comprises the steps of:

-   a) dissolving benzoylchloride or substitute carboxylic acid with    substituted benzothiazole selected from the group consisting of    2-amino-6-nitrobenzothiazole, 2,6-diaminobenzothiazole in dry DMF to    obtain reaction mixture;-   b) treating a reaction mixture as obtained in step (a) with    triethylamine or 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide    hydrochloride (EDCI) and N,N-dimethylaminopyridine (DMAP) followed    by stirring at 0° C. to 30° C. for a period ranging between 12-14    hrs to obtain compound of 8(a-d) and compounds 5(a-w);-   c) dissolving compounds 5 (a-w) as obtained in step (b) in THF    followed by adding ammonium formate and Zn dust;-   d) stirring the reaction mixture as obtained in step (c) at    temperature ranging between 25-30° C. for a period ranging between    30 min to 90 min. to obtain corresponding amine;-   e) reacting corresponding amine as obtained in step (d) with dry    DMF, 5-nitro-2-furoicacid, EDC    (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide) and HoBt    (1-hydroxy-1,2,3-benzotriazole) followed by stirring at temperature    ranging between 25-30° C. for a period ranging between 12-14 hrs to    obtain compounds 6a-w.

In another embodiment of the present disclosure, a process whereinsubstituted carboxylic acid used in step (a) is selected from the groupconsisting of 5-Nitro-2-furancarboxylic acid,1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid and1-methyl-5-nitro-1H-imidazole-2-carboxylic acid.

In another embodiment of the present disclosure, wherein yield of thecompounds ranges between 50%-89%.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 discloses the process for the synthesis of new benzothiazolecompounds as anti-tubercular agents producing the new compounds ofbenzothiazole scaffold in good yields. Reagents and conditions: (i)hydrazine hydrate, N₂H₄.HCl, glycol, 140° C., 4 h; (ii)5-nitro-2-furaldehyde/5-nitro-2-thiophenaldehyde, EtOH, cat AcOH,reflux, 2 h; (iii) Et₃N, 5-nitro-2-furoic acid chloride, N,N-dimethylformamide, THF (tetrahydrofuran), 25° C., 12 h; (iv) aryl acid,N,N-dimethyl formamide, EDC(1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide), HoBT(1-hydroxy-1,2,3-benzotriazole), 12 h; (v) Zn-ammonium formate, MeOH,rt, 1 h; (vii) 5-nitro-2-furoic acid, N,N-dimethyl formamide, EDC(1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide), HoBt(1-hydroxy-1,2,3-benzotriazole), 12 h; (viii) nitro-hetero acids,N,N-dimethyl formamide, EDC(1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide), HoBt(1-hydroxy-1,2,3-benzotriazole), 12 h.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The process for the synthesis of new benzothiazole compounds asanti-tubercular agents produces the new compounds of benzothiazolescaffold in good yields, wherein the key step for the synthesis of thesecompounds is by direct coupling of substituted heteroaromatic aldehydeswith 2-hydrazido benzothiazole scaffold via amide linkage and hydrazinebridges.

Thus the present disclosure provides new class of benzothiazolecompounds, which were synthesized by coupling reaction manner.

A program was initiated in the laboratory for the design and synthesisof new benzothiazole compounds with enhanced anti-tubercular activityagainst sensitive and MDR-resistant strains. In these efforts newbenzothiazole scaffold based congeners have been synthesized andevaluated for their cytotoxicity and anti-tubercular potency compared torifampicin. The synthesis of these compounds has been carried out asdescribed in the Scheme-1 using substituted 2-amino benzothiazoles asstarting material.

EXPERIMENTAL

The following examples are given by way of illustration of the presentdisclosure and therefore should not be construed to limit the scope ofthe present disclosure.

Example 1 General Procedure for the Synthesis of Synthesis ofAryl/heterocyclic aldehyde-2-(1,3-benzothiazol-2-yl)hydrazones (3a-p)

Aryl or heterocyclic aldehydes (1 mmol) and 2-hydrazeno-benzothiazoles(1 mmol) were dissolved in ethanol (10 ml), to this resulting mixturecatalytic amount of acetic acid (1 ml) was added and the mixture wasstirred at 70° C. for 2 h, and the formed precipitate was collected byfiltration and washed with cold methanol (3×30 mL) and chloroform (2×20mL). The collected precipitate was recrystalysed from hot methanolaffords hydrazones.

5-nitro-2-furaldehyde 2-(1,3-benzothiazole-2-yl)hydrazone (3a)

The compound 3a was prepared according to above described method byusing 5-nitro-2-furancarboxaldehyde (140 mg, 1 mmol) and2-hydrazeno-benzothiazoles (165 mg, 1 mmol) at 70° C. for 2 h (yield 244mg, 85%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.3 (bs, 1H), 7.84 (m, 1H), 7.8 (s, 1H),7.7 (d, 1H, J=3.7 Hz), 7.60 (d, 1H), 7.43 (m, 1H, J=2.9, 8.0 Hz), 7.22(d, 1H, J=8.7 Hz), 6.90 (d, 1H, J=3.7 Hz); ESIMS: m/z 288 (M)⁺, 289(M+H)⁺.

Example 2 5-nitro-2-thiophenecarbaldehyde2-(1,3-benzothiazol-2-yl)hydrazone (3b)

The compound 3b was prepared according to above described method byusing 5-nitro-2-thiophencarboxaldehyde (156 mg, 1 mmol) and2-hydrazino-benzothiazoles (165 mg, 1 mmol) at 70° C. for 2 h (yield 258mg, 85%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.0 (bs, 1H), 7.83 (d, 1H, J=4.3 Hz), 7.79(s, 1H), 7.35 (d, 1H, J=8.0 Hz), 7.19-7.15 (m, 3H, J=4.3, 7.1 Hz), 7.00(dd, 1H, J=8.0, 2.9 Hz); ESIMS: m/z 304 (M)⁺, 305 (M+H)⁺.

Example 3 5-nitro-2-furaldehyde2-(6-methyl-1,3-benzothiazol-2-yl)hydrazone (3c)

The compound 3c was prepared according to above described method byusing 5-nitro-2-furancarboxaldehyde (140 mg, 1 mmol) and2-hydrazino-6-methyl-benzothiazoles (178 mg, 1 mmol) at 70° C. for 2 h(yield 268 mg, 89%).

¹H NMR (DMSO-d₆, 200 MHz): δ 11.4 (bs, 1H), 7.90 (s, 1H), 7.56 (d, 1H,J=3.7 Hz), 7.30 (d, 1H, J=9.0 Hz), 7.24 (d, 1H, J=2.2 Hz), 7.01 (d, 1H,J=3.7 Hz), 6.84 (dd, 1H, J=9.0, 2.2 Hz), 2.76 (s, 3H); ESIMS: m/z 302(M)⁺, 303 (M+H)⁺.

Example 4 5-nitro-2-thiophenecarbaldehyde2-(6-methyl-1,3-benzothiazol-2-yl)hydrazone (3d)

The compound 3d was prepared according to above described method byusing 5-Nitro-2-nitrothiophen carboxaldehyde (157 mg, 1 mmol) and2-hydrazino-6-methyl-benzothiazoles (178 mg, 1 mmol) at 70° C. for 2 h(yield 276 mg, 87%).

¹H NMR (DMSO-d₆, 200 MHz): δ 11.0 (bs, 1H), 7.80 (s, 1H), 7.81 (d, 1H,J=4.7 Hz), 7.32 (d, 1H, J=9.0 Hz), 7.25 (d, 1H, J=2.2 Hz), 7.17 (d, 1H,J=4.7 Hz), 7.00 (dd, 1H, J=9.0, 2.25 Hz), 2.74 (s, 3H); ESIMS: m/z 318(M)⁺.

Example 5 5-nitro-2-furaldehyde2-(6-methoxy-1,3-benzothiazol-2-yl)hydrazone (3e)

The compound 3e was prepared according to above described method byusing 5-nitro-2-furancarboxaldehyde (140 mg, 1 mmol) and2-hydrazino-6-methoxy-benzothiazoles (195 mg, 1 mmol) at 70° C. for 2 h(yield 283 mg, 89%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.4 (bs, 1H), 7.96 (s, 1H), 7.58 (d, 1H,J=3.7 Hz), 7.35 (d, 1H, J=9.0 Hz), 7.27 (d, 1H, J=2.2 Hz), 6.96 (d, 1H,J=3.7 Hz), 6.84 (dd, 1H, J=9.0, 2.2 Hz), 3.76 (s, 3H); ESIMS: m/z 318(M)⁺, 319 (M+H)⁺.

Example 6 5-nitro-2-thiophenecarbaldehyde2-(6-methoxy-1,3-benzothiazol-2-yl)hydrazone (3f)

The compound 3f was prepared according to above described method byusing 5-Nitro-2-nitrothiophen carboxaldehyde (157 mg, 1 mmol) and2-hydrazino-6-methoxy-benzothiazoles (195 mg, 1 mmol) at 70° C. for 2 h(yield 267 mg, 80%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.0 (bs, 1H), 7.89 (s, 1H), 7.82 (d, 1H,J=4.7 Hz), 7.30 (d, 1H, J=9.0 Hz), 7.27 (d, 1H, J=2.2 Hz), 7.19 (d, 1H,J=4.7 Hz), 6.84 (dd, 1H, J=9.0, 2.25 Hz), 3.76 (s, 3H); ESIMS: m/z 334(M)⁺, 334 (M+H)⁺.

Example 7 5-nitro-2-furaldehyde2-(6-trifluoromethyl-1,3-benzothiazol-2-yl)hydrazone (3g)

The compound 3g was prepared according procedure described for 3a byemploying 5-nitrofuran aldehyde (141 mg, 1 mmol) and2-hydrazino-6-trifluoromethyl-benzothiazole (233 mg, 1 mmol) at 70° C.for 2 h (yield 302 mg, 85%).

¹H NMR (DMSO-d₆, 200 MHz): δ 11.5 (bs, 1H), 7.84 (m, 1H, J=4.3 hz), 7.60(d, 1H), 7.58 (d, 1H, J=3.7 Hz), 7.43 (m, 1H, J=2.9, 8.0 Hz), 7.22 (d,1H, J=8.7 Hz), 6.9 (d, 1H, J=3.7 Hz); ESIMS: m/z 356 (M)⁺, 357 (M+H)⁺.

Example 8 5-nitro-2-thiophenecarbaldehyde2-(6-trifluoromethyl-1,3-benzothiazol-2yl)hydrazone (3h)

The compound 3h was prepared according procedure described for 3a byemploying 5-nitrothiophen aldehyde (157 mg, 1 mmol) and2-hydrazino-6-trifluoromethyl-benzothiazole (233 mg, 1 mmol) at 70° C.for 2 h (yield 312 mg, 84%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.3 (bs, 1H), 7.84-7.82 (m, 2H, J=4.3 Hz),7.60 (d, 1H), 7.43 (m, 1H, J=2.9, 8.0 Hz), 7.22 (d, 1H, J=8.7 Hz), 7.19(d, 1H, J=4.38 Hz); ESIMS: m/z 372 (M+H)⁺.

Example 9 5-nitro-2-furaldehyde2-(6-trifluoromethoxy-1,3-benzothiazol-2yl)hydrazone (3i)

The compound 3i was prepared according procedure described for 3a byemploying 5-nitrofuran aldehyde (141 mg, 1 mmol) and2-hydrazino-6-trifluoromethoxy-benzothiazole (249 mg, 1 mmol) at 70° C.for 2 h (yield 298 mg, 80%).

¹H NMR (DMSO-d₆, 200 MHz): δ 8.42 (bs, 1H), 7.44-7.41 (m, 2H), 7.36 (d,1H), 7.27 (d, 1H, J=2.4 Hz), 7.30 (d, 1H, J=3.9 Hz), 7.14 (d, 1H, J=8.6Hz), 6.48 (d, 1H, J=3.9 Hz); ESIMS: m/z 373 (M+H)⁺.

Example 10 5-nitro-2-thiophenecarbaldehyde2-(6-trifluoromethoxy-1,3-benzothiazol-2yl)hydrazone (3j)

The compound 3j was prepared according procedure described for 3a byemploying 5-nitrothiophen aldehyde (157 mg, 1 mmol) and2-hydrazino-6-trifluoromethoxy-benzothiazole (249 mg, 1 mmol) at 70° C.for 2 h (yield 219 mg, 75%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.7 (bs, 1H), 8.14-8.10 (m, 2H, J=7.7, 4.3Hz), 7.83 (m, 1H), 7.51 (d, 1H, J=4.5 Hz), 7.35-7.30 (m, 2H), 6.93 (dd,1H, J=2.4, 8.7 Hz), 3.77 (s, 3H); ESIMS: m/z 388 (M+H)⁺.

Example 11 5-nitro-2-furaldehyde2-(6-fluoro-1,3-benzothiazol-2yl)hydrazone (3k)

The compound 3k was prepared according procedure described for 3a byemploying 5-nitrofuran aldehyde (157 mg, 1 mmol) and2-hydrazino-6-fluoro-benzothiazole (183 mg, 1 mmol) at 70° C. for 2 h(yield 230 mg, 75%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.5 (bs, 1H), 7.86 (s, 1H), 7.57 (d, 1H,J=3.7 Hz), 7.39 (d, 1H, J=9.0 Hz), 7.28 (d, 1H, J=2.2 Hz), 7.02 (d, 1H,J=3.7 Hz), 6.86 (dd, 1H, J=9.0, 2.2 Hz); ESIMS: m/z 307 (M+H)⁺.

Example 12 5-nitro-2-thiophenecarbaldehyde2-(6-chloro-1,3-benzothiazol-2yl)hydrazone (3n)

The compound 3n was prepared according procedure described for 3a byemploying 5-nitrothiophen aldehyde (157 mg, 1 mmol) and2-hydrazino-6-chloro-benzothiazole (199 mg, 1 mmol) at 70° C. for 2 h(yield 287 mg, 85%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.0 (bs, 1H), 7.84-7.82 (m, 2H, J=4.3 Hz),7.60 (d, 1H), 7.43 (m, 1H, J=2.9, 8.0 Hz), 7.22 (d, 1H, J=8.7 Hz), 7.19(d, 1H, J=4.3 Hz); ESIMS: m/z 338 (M)⁺.

Example 13 5-nitro-2-furaldehyde2-(6-nitro-1,3-benzothiazol-2yl)hydrazone (3o)

The compound 3o was prepared according procedure described for 3a byemploying 5-nitrofuran aldehyde (141 mg, 1 mmol) and2-hydrazino-6-nitro-benzothiazole (210 mg, 1 mmol) at 70° C. for 2 h(yield 283 mg, 85%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.7 (bs, 1H), 8.10 (s, 1H), 7.71 (d, 1H,J=3.9 Hz), 7.43 (m, 1H), 7.30 (m, 1H, J=7.8 Hz), 7.15-7.12 (m, 2H,J=2.4, 6.8 Hz); ESIMS: m/z 333 (M)⁺.

Example 14 5-nitro-2-thiophenecarbaldehyde2-(6-nitro-1,3-benzothiazol-2yl)hydrazone (3p)

The compound 3p was prepared according procedure described for 3a byemploying 5-nitrothiophen aldehyde (157 mg, 1 mmol) and2-hydrazino-6-nitro-benzothiazole (210 mg, 1 mmol) at 70° C. for 2 h(yield 303 mg, 87%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.0 (bs, 1H), 8.15-8.09 (m, 2H, J=4.7 Hz),7.43 (m, 1H), 7.30 (m, 1H, J=7.8 Hz), 7.15-7.12 (m, 2H, J=2.4, 6.8 Hz);ESIMS: m/z 349 (M+H)⁺.

General Procedure for Preparation ofN-(6-halo/alkyl-1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide(4a-h)

5-Nitro-2-furancarboxylic acidchloride (300 mg, 1 mmol) and2-hydrazino-benzothiazole (1 mmol) in dry DMF (5 mL) were treated withtriethylanine (3 mmol) followed by N,N-dimethylaminopyridine (DMAP) (730mg, 2.5 mmol), and the resulting solution was stirred for 1 h at 0° C.and stirring continued at 25° C. for 11 h. Then pour the reaction intochloroform (70 mL), washed with washed with 10% NaHCO₃ (sodiumbicarbonate) solution (2×20 mL). The organic phage was dried over Na₂SO₄(sodium sulphate), concentrated in vacuum followed by columnpurification with ethyl acetate hexane system affords correspondingamides.

Example 15 N′2-(1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide(4a)

The compound 4a was prepared according to above described method byusing 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and2-hydrazino-benzothiazole (300 mg, 1.5 mmol) which stirred for 1 h at 0°C. and stirring continued at 25° C. for 11 h (yield 245 mg, 85%).

¹H NMR (DMSO-d₆, 200 MHz): δ 13.7 (bs, 1H), 9.0 (bs, 1H), 8.42-8.40 (m,1H), 8.20 (m, 1H), 7.88-7.82 (m, 2H), 7.73-7.68 (m, 2H); ESIMS: m/z 304(M)⁺.

Example 16N′2-(6-methyl-1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide (4b)

The compound 4b was prepared according to above described method byusing 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and2-hydrazino-6-methylbenzothiazole (179 mg, 1 mmol) which stirred for 1 hat 0° C. and stirring continued at 25° C. for 11 h (yield 216 mg, 85%).

¹H NMR (DMSO-d₆, 200 MHz): δ 11.0 (bs, 1H), 8.02 (bs, 1H), 7.76 (d, 1H,J=3.9 Hz), 7.45 (m, 1H), 7.37 (d, 1H, J=8.1 Hz), 7.12 (d, 1H, J=3.7 Hz),6.98 (dd, 1H, J=2.4, 8.6 Hz), 2.47 (s, 3H); ESIMS: m/z 319 (M+H)⁺.

Example 17N′2-(6-methoxy-1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide (4c)

The compound 4c was prepared according to above described method byusing 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and2-hydrazino-6-methoxybenzothiazole (260 mg, 1 mmol) which stirred for 1h at 0° C. and stirring continued at 25° C. for 11 h (yield 283 mg,85%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.0 (bs, 1H), 8.02 (bs, 1H), 7.76 (d, 1H,J=3.9 Hz), 7.45 (m, 1H), 7.40 (d, 1H, J=8.1 Hz), 7.12 (d, 1H, J=3.7 Hz),6.93 (dd, 1H, J=2.4, 8.6 Hz), 3.77 (s, 3H); ESIMS: m/z 334 (M)⁺.

Example 18N′2-(6-trifluoromethyl-1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide(4d)

The compound 8c was prepared according to above described method byusing 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and2-hydrazino-6-trifluoromethylbenzothiazole (419 mg, 1 mmol) whichstirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h(yield 279 mg, 75%).

¹H NMR (DMSO-d₆, 200 MHz): δ 11.3 (bs, 1H), 9.94 (bs, 1H), 7.80 (d, 1H,J=3.9 Hz), 7.55 (m, 1H, J=7.8 Hz), 7.38 (m, 1H, J=7.8 Hz), 6.88 (dd, 1H,J=9.1, 2.6 Hz), 6.81 (d, 1H, J=3.9 Hz); ESIMS: m/z 373 (M+H)⁺.

Example 19N′2-(6-trifluoromethoxy-1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide(4e)

The compound 4e was prepared according to above described method byusing 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and2-hydrazino-6-trifluoromethoxybenzothiazole (319 mg, 1.5 mmol) whichstirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h(yield 287 mg, 87%).

¹H NMR (DMSO-d₆, 200 MHz): δ 12.5 (bs, 1H), 8.2 (bs, 1H), 7.9 (d, 1H),7.7 (d, 1H, J=3.9 Hz), 7.54 (m, 1H), 7.50 (d, 1H, J=8.1 Hz), 7.12 (d,1H, J=3.7 Hz); ESIMS: m/z 388 (M)⁺.

Example 20N′2-(6-fluoromethoxy-1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide(4f)

The compound 4f was prepared according to above described method byusing 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and2-hydrazino-6-fluoromethoxybenzothiazole (274 mg, 1.5 mmol) whichstirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h(yield 242 mg, 75%).

¹H NMR (DMSO-d₆, 200 MHz): δ 11.4 (bs, 1H), 8.18 (bs, 1H), 7.84 (d, 1H),7.73 (d, 1H, J=3.9 Hz), 7.48 (m, 1H), 7.40 (d, 1H, J=8.1 Hz), 7.10 (d,1H, J=3.7 Hz); ESIMS: m/z 323 (M+H)⁺.

Example 21N′2-(6-chloromethoxy-1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide(4g)

The compound 4g was prepared according to above described method byusing 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and2-hydrazino-6-chloromethoxybenzothiazole (298 mg, 1.5 mmol) whichstirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h(yield 237 mg, 70%).

¹H NMR (DMSO-d₆, 200 MHz): δ 11.3 (bs, 1H), 8.14 (bs, 1H), 7.82 (d, 1H),7.71 (d, 1H, J=3.9 Hz), 7.44 (m, 1H), 7.39 (d, 1H, J=8.1 Hz), 7.10 (d,1H, J=3.7 Hz); ESIMS: m/z 339 (M+H)⁺.

Example 22N′2-(6-Nitro-1,3-benzothiazol-2yl)-5-nitro-2-furanecarbohydrazide (4h)

The compound 4h was prepared according to above described method byusing 5-nitro-2-furancarboxylic acid chloride (430 mg, 1.5 mmol) and2-hydrazino-6-nitrobenzothiazole (290 mg, 1 mmol) which stirred for 1 hat 0° C. and stirring continued at 25° C. for 11 h (yield 283 mg, 87%).

¹H NMR (DMSO-d₆, 200 MHz): δ 8.2 (bs, 1H), 8.0 (d, 1H), 7.9 (m, 1H),7.76 (d, 1H, J=3.9 Hz), 7.45 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=3.7 Hz);ESIMS: m/z 244 (M)⁺.

Example 23 N2-[2-(benzoylamino)-1,3-benzothiazol-6yl]-5-nitrofuramide(6a)

Benzoylchloride (140 mg, 1 mmol) and 2-amino-6-nitrobenzothiazole (1h)(195 mg, 1 mmol) in dry DMF (5 mL) were treated with triethylanine(0.418 mL, 3 mmol) followed by N,N-dimethylaminopyridine (DMAP) (305 mg,2.5 mmol), and the resulting solution was stirred was stirred for 1 h at0° C. and stirring continued at 25° C. for 11 h. Then the reactionmixture poured on to crushed ice and stirred well, formed precipitatefiltered and washed with cold dichloromethane (20 mL), washed with 10%NaHCO₃ solution (2×20 mL). The solid was recrystallization by using THFaffording compound 5a as a yellow solid (Yield: 174 mg, 55%)

To a solution of (5a) (300 mg, 1 mmol) in THF (10 ml), ammonium formate(130 mg, 2 mmol) was added and zinc dust (15 mg, 0.2 mmol) was added andstirred for 30 minutes at room temperature. After the completion ofreaction as indicated by TLC, the solvent was removed under reducedpressure, neutralized with saturated sodium bicarbonate solution andextracted with chloroform. The solvent was removed under reducedpressure to give the desired amino intermediate. This was directly usedfor the further step.

To a solution of 5-nitro-2-furoicacid (157 mg, 1 mmol) and triethylamine(0.25 mL, 2 mmol) in dry DMF (5 mL),1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (155 mg, 1 mmol) and1-hydroxy-1,2,3-benzotriazole (HoBt) (135 mg, 1 mmol) were added. Afterfive minutes, previously prepared amine (215 mg, 0.8 mmol) was added tothe reaction mixture and stirred at room temperature (25° C.) for 12hrs. After the completion of reaction as indicated by TLC, ice coldwater (15 mL) was added to the reaction mixture, filtered theprecipitate and gave wash with cold THF to give the desired product(6a). Yield 204 mg, 50%; ¹H NMR (DMSO-d₆) δ 12.45 (bs, 1H, —NH), 10.52(bs, 1H, —NH), 8.37 (s, 1H), 8.16 (d, 2H), 7.78 (dd, 1H), 7.67 (d, 1H),7.60 (d, 1H), 7.57 (d, 1H), 7.55 (d, 1H), 7.49 (t, 2H); MS (ESI) m/z 409(M+H)⁺.

Example 24N2-{2-[(4-fluorobenzoyl)amino]-1,3-benzothiazol-6yl}-5-nitrofuramide(6f)

The compound 6f was prepared according to the above described methodusing compound 5f (317 mg, 1 mmol) and 5-nitro-2-furoicacid (157 mg, 1mmol). Yield 235 mg, 55%; ¹H NMR (DMSO-d₆) δ 12.4 (bs, 1H, —NH), 10.5(bs, 1H, —NH), 8.37 (s, 1H), 8.18 (d, 2H), 7.78 (d, 1H), 7.69 (d, 1H),7.57 (d, 1H), 7.55 (d, 1H), 7.35 (d, 2H); MS (ESI) m/z 427 (M+H)⁺.

Example 25N2-{2-[(4-chlorobenzoyl)amino]-1,3-benzothiazol-6yl}-5-nitrofuramide(6g)

The compound 6g was prepared according to the above described methodusing compound 5g (333 mg, 1 mmol) and 5-nitro-2-furoicacid (157 mg, 1mmol). Yield 221 mg, 50%; ¹H NMR (DMSO-d₆) δ 11.4 (bs, 1H, —NH), 9.51(bs, 1H, —NH), 8.37 (s, 1H), 7.92 (d, 2H), 7.78 (d, 1H), 7.69 (d, 1H),7.57 (d, 1H), 7.55 (d, 1H), 7.48 (d, 2H); MS (ESI) m/z 443 (M+H)⁺.

Example 26N2-{2-[(2,4-difluorobenzoyl)amino]-1,3-benzothiazol-6yl}-5-nitrofuramide(6i)

The compound 6i was prepared according to the above described methodusing compound 5i (335 mg, 1 mmol) and 5-nitro-2-furoicacid (157 mg, 1mmol). Yield 244 mg, 55%; ¹H NMR (DMSO-d₆) δ 10.4 (bs, 1H, —NH), 9.51(bs, 1H, —NH), 8.37 (s, 1H), 7.99-7.97 (m, 1H), 7.78 (d, 1H), 7.69 (d,1H), 7.57 (d, 1H), 7.55 (d, 1H), 7.20 (m, 1H), 6.85 (s, 1H); MS (ESI)m/z 445 (M+H)⁺.

Example 27N4-(6-{[(5-nitrofuryl)carbonyl]amino}-1,3-benzothiazol-2-yl)isonicotinamide(6n)

The compound 6n was prepared according to the above described methodusing compound 5n (300 mg, 1 mmol) and 5-nitro-2-furoicacid (157 mg, 1mmol). Yield 220 mg, 54%; ¹H NMR (DMSO-d₆) δ 11.4 (bs, 1H, —NH), 9.51(bs, 1H, —NH), 8.73-8.71 (m, 2H), 8.37 (s, 1H), 7.84-7.83 (m, 2H), 7.78(d, 1H), 7.69 (d, 1H), 7.57 (d, 1H), 7.55 (d, 1H); MS (ESI) m/z 410(M+H)⁺.

Example 28N3-(6-{[(5-nitrofuryl)carbonyl]amino}-1,3-benzothiazol-2-yl)nicotinamide(6o)

The compound 6O was prepared according to the above described methodusing compound 5O (300 mg, 1 mmol) and 5-nitro-2-furoicacid (157 mg, 1mmol). Yield 220 mg, 54%; ¹H NMR (DMSO-d₆) δ 11.4 (bs, 1H, —NH), 9.51(bs, 1H, —NH), 9.10-9.08 (m, 1H), 8.37 (s, 1H), 8.67-8.66 (m, 1H),8.41-8.38 (m, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.65-7.64 (m, 1H), 7.57(d, 1H), 7.55 (d, 1H); MS (ESI) m/z 410 (M+H)⁺.

Example 29N2-(6-{[(5-nitrofuryl)carbonyl]amino}-1,3-benzothiazol-2-yl)pyrazinecarboxamide(6p)

The compound 6p was prepared according to the above described methodusing compound 5p (301 mg, 1 mmol) and 5-nitro-2-furoicacid (157 mg, 1mmol). Yield 266 mg, 65%; ¹H NMR (DMSO-d₆) δ 12.0 (bs, 1H, —NH), 10.9(bs, 1H, —NH), 8.95 (s, 1H), 8.68 (d, 1H), 8.48 (d, 1H), 8.35 (s, 1H),7.80 (d, 1H), 7.71 (d, 1H), 7.65 (d, 1H), 7.51 (d, 1H); MS (ESI) m/z 411(M+H)⁺.

Example 30N2-(2-{[(E)-3-(4-fluorophenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide(6v)

The compound 6v was prepared according to the above described methodusing compound 5v (343 mg, 1 mmol) and 5-nitro-2-furoicacid (157 mg, 1mmol). Yield 235 mg, 54%; ¹H NMR (DMSO-d₆) δ 11.4 (bs, 1H, —NH), 9.51(bs, 1H, —NH), 8.73-8.71 (m, 2H), 8.51 (d, 1H), 8.37 (s, 1H), 7.78 (d,1H), 7.69 (d, 1H), 7.57 (d, 1H), 7.55 (d, 1H), 7.45-7.43 (m, 2H), 6.52(d, 1H); MS (ESI) m/z 453 (M+H)⁺.

Example 31 Synthesis ofN2-(2-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide(8a)

5-Nitro-2-furancarboxylic acid (300 mg, 2 mmol) and2,6-diaminobenzothiazole (7) (165 mg, 1 mmol) in dry DMF (5 mL) weretreated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDCI) 98% (310 mg, 2 mmol) followed byN,N-dimethylaminopyridine (DMAP) (305 mg, 2.5 mmol), and the resultingsolution was stirred for 14 h at room temperature. Then the reactionmixture poured on to crushed ice and stirred well, formed precipitatefiltered and washed with cold dichloromethane (20 mL), washed with 10%NaHCO₃ solution (2×20 mL), followed by recrystalyzed from methanolaffords pure compound (8a). Yield 287 mg, 65%.

¹H NMR (DMSO-d₆, 200 MHz): δ 8.02 (bs, 1H), 7.80 (d, 2H, J=3.9 Mz), 7.7(m, 1H), 7.60 (d, 2H, J=8.1 Hz), 7.65 (d, 2H, J=3.7 Hz); ESIMS: m/z 443(M)⁺.

Example 32N2-(2-{[(1-methyl-4-nitro-1H-2-pyrrolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-4-nitro-1H-2-pyrrolcarboxamide(8b)

The compound 8b was prepared according to the above described methodusing compound 7 (165 mg, 1 mmol) and1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid (340 mg, 2 mmol). Yield290 mg, 60%; ¹H NMR (DMSO-d₆) δ 10.9 (bs, 1H, —NH), 8.54 (s, 1H), 7.95(s, 2H), 7.74-7.71 (m, 2H), 7.50 (s, 2H), 3.96 (s, 6H); ESIMS: m/z 470(M+H)⁺.

Example 33N2-(2-{[(1-methyl-5-nitro-1H-2-imadazolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-5-nitro-1H-2-imadazolecarboxamide(8c)

The compound 8c was prepared according to the above described methodusing compound 7 (165 mg, 1 mmol) and1-methyl-5-nitro-1H-imidazole-2-carboxylic acid (342 mg, 2 mmol). Yield300 mg, 63%; ¹H NMR (DMSO-d₆) δ 9.51 (bs, 1H, —NH), 8.54 (s, 1H), 8.20(s, 2H), 7.74-7.71 (m, 2H), 3.76 (s, 6H); ESIMS: m/z 472 (M+H)⁺.

Example 34N2-(2-{[(1-methyl-3-nitro-1H-2-pyrazolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-3-nitro-1H-2-pyrazolecarboxamide(8d)

The compound 8d was prepared according to the above described methodusing compound 7 (165 mg, 1 mmol) and1-methyl-3-nitro-1H-pyrazole-5-carboxylic acid (342 mg, 2 mmol). Yield258 mg, 55%; ¹H NMR (DMSO-d₆) δ 9.51 (bs, 1H, —NH), 8.54 (s, 1H),7.74-7.71 (m, 2H), 6.50 (s, 2H), 3.96 (s, 6H); ESIMS: m/z 472 (M+H)⁺.

Biological Data

1. Antimycobacterial Activity

The compounds 3a-f, 4a-h, 6a,f,g,i,o,p,q,w, and 8a have been evaluatedor the antimycobacterial activity and the results are summarized inTable 1. All compounds were initially screened against M. tuberculosisH₃₇Rv at the single concentration of 16 (μg/mL). The active compoundsfrom this screening were further tested for Minimum InhibitoryConcentration (MIC) determination using a broth microdilution assay.Compounds demonstrating at least 90% inhibition in the primary screenwere retested at lower concentrations by serial dilution against M.tuberculosis H₃₇Rv to determine the actual MIC, using the NitrateReductase Assay (NRA). The growth in the microtitre plate is indicatedby the change in color to pink detected by the addition of NRA reagent.The MIC is defined as the lowest concentration of the compound showingno change in the color relative to controls. Rifampicin and Isoniazidwere used as reference drugs. All these compounds have shown activitybetween 0.5→16 μg/mL. Among these compounds nitrofurane derivedbenzothiazoles (3j, 4e, 6a, 6f, 6g, 6i, 6p, 6w and 8a) have shown goodin vivo anti-mycobacterial activity (0.5-8 μg/mL).

TABLE 1 Antimycobacterial activity of compounds 3a-f, 4, 6a, f, g, i, o,p, q, w, and 8a against M. tuberculosis H37Rv (MIC in μg/mL). Comp MIC(μg/mL) C log P^(c) CMR^(d) M. Wt Mol. For 3a >16 3.24 7.63 288.28C₁₂H₈N₄O₃S 3b >16 3.78 8.23 304.01 C₁₂H₈N₄O₂S₂ 3c >16 3.74 8.10 302.04C₁₃H₁₀N₄O₃S 3d >16 4.28 8.69 318.37 C₁₃H₁₀N₄O₂S₂ 3e >16 3.54 8.25 318.31C₁₃H₁₀N₄O₄S 3f >16 4.07 8.85 334.37 C₁₃H₁₀N₄O₃S₂ 3g >16 4.19 8.14 356.28C₁₃H₇F₃N₄O₃S 3h >16 4.72 8.74 372.35 C₁₃H₇F₃N4O₂S₂ 3i >16 4.65 8.30372.28 C₁₃H₇F₃N₄O₄S 3j 1 5.18 8.89 388.34 C₁₃H₇F₃N₄O₃S₂ 3k >16 3.38 7.65306.27 C₁₂H₇FN₄O₃S 3l >16 3.91 8.24 322.34 C₁₂H₇FN₄O₂S₂ 3m 16 3.95 8.13322.73 C₁₂H₇ClN₄O₃S 3n >16 4.48 8.72 338.79 C₁₂H₇ClN₄O₂S₂ 3o 16 3.098.26 333.28 C₁₂H₇N₅O₅S 3p >16 3.62 8.84 349.35 C₁₂H₇N₅O₄S₂ 4a >16 1.417.54 304.28 C₁₂H₈N₄O₄S 4b >16 1.91 8.01 318.03 C₁₃H₁₀N₄O₄S 4c >16 1.708.16 334.31 C₁₃H₁₀N₄O₅S 4d >16 2.32 8.05 372.28 C₁₃H₇F₃N₄O₄S 4e 2 2.818.21 388.28 C₁₃H₇F₃N₄O₅S 4f >16 1.55 7.56 322.27 C₁₂H₇FN₄O₄S 4g >16 2.128.03 337.98 C₁₂H₇ClN₄O₄S 4h 16 1.21 8.15 349.09 C₁₂H₇N₅O₈S 6a 1 3.6910.55 408.05 C₁₉H₁₂N₄O₅S 6f 0.5 4.89 11.2 492.03 C₂₀H₁₁F₃N₄O₆S 6g 0.53.86 10.57 426.04 C₁₉H₁₁FN₄O₅S 6i 0.5 3.47 11.66 472.02 C₂₀H₁₃ClN₄O₆S 6o4.0 3.73 11.15 452.39 C₂₀H₁₂N₄O₇S 6p 1 2.48 10.3 409.04 C₁₈H₁₁N₅O₅S 6q8.0 2.83 10.34 409.04 C₁₈H₁₁N₅O₅S 6w 2.0 5.59 12.27 502.42 C₂₂H₁₃F₃N₄O₅S8a 2 2.72 10.38 443.35 C₁₇H₉N₅O₈S RMP^(a) 0.25 INH^(b) 0.5^(a)Rifampcin, ^(b)Isoniazid; ^(c)C log P (Hydrophobicity); and ^(d)CMR(molar refractivity) was calculated using the Chem Draw Ultra, version9.02. Cytotoxicity Assay

The potent compounds 3j, 4e, 6a, 6f, 6g, 6i, and 6p were evaluated forcytotoxic effect on AML-12 cell lines using MTT assay, in a 96 wellplate format. Cells were incubated in Dulbecco's Modified Eagle's Medium(DMEM) containing 10% fetal calf serum (FCS) with the test material(2-100 μg/ml) for 24 hrs at 37° C. in CO₂ incubator. After thecompletion of incubation3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) wasadded and cells were further incubated for 3 h at 37° C. in CO₂incubator. Formation of formazan salt by mitochondrial dehydrogenases,and was determined by Elisa reader at 565 nm (Multiskan Spectrum; ThermoElectron Corporation, USA). The percentage cytotoxicity was calculatedwith respect to the untreated cells. The results were summarized inTable 2.

TABLE 2 Cytotoxicity assay on cell line AML-12 (μg/mL) Compound codeCytotoxicity 3j >100 4e >100 6a >100 6f >100 6g >100 6i >100 6o >1006p >100 6q >100 6w >1003. In Vivo Efficacy Studies

The Compounds 3j, 4e, 6a, 6f, 6g, 6i, 6p, 6w and 8a demonstrated good invitro activity against M. tuberculosis isolates and drug resistancestrains. The active compounds of the series has been subjected tocytotoxicity assay (MTT assay), the tested compounds does not show anypathological effects. Subsequently, compounds 6f, 6g and 6i were testedfor in vivo efficacy against M. tuberculosis at a dose of 25 mg/kg(Table 3) in six week-old female Swiss albino mice. In this model themice were infected through intra nasally with 25 μL volume containing1.5×10⁶ CFU/mouse of viable M. tuberculosis (H37Rv). Drug treatmentbegan after inoculation of the animal with microorganism and continuedfor 10 days by intraperitoneal route. After 35 days of post-infection,the left lungs was aseptically removed and ground in a tissuehomogenizer, and the number of viable organisms was determined by serial10-fold dilutions and subsequent inoculation onto 7H10 agar plates.Cultures were incubated at 37° C. in ambient air for 4 weeks prior tocounting. Bacterial counts were measured and compared with the countsfrom negative (untreated) controls (Mean culture forming units (CFU) inlung: 6.3±0.22). Compound 6f, 6g and 6i dose exhibited bacteriostaticactivities and maintained the CFU load as the early control anddecreased the bacterial load in lung 1.0 protections with late control,respectively, and was considered to be promising in reducing bacterialcount in lung tissues.

TABLE 3 In vivo efficacy studies of compounds 6f, 6g and 6i against M.tuberculosis in lungs of infected Mice. S. No Nb Treatment groupa Log10CFU/left Lung 1 8 Early Control 6.0 ± 0.25 2 7c Late Control 7.3 ± 0.373 7c Rifampcin (20 mg/kg) 2.0 ± 0.41 4 7c Comp. (6f) 25 (mg/kg) 6.0 ±0.13 5 7c Comp. (6g) 25 (mg/kg) 6.1 ± 0.48 6 7c Comp (6i) 25 (mg/kg) 6.3± 0.37 aTreatment was started 1 week after mice received ≈ 1 × 106viable mycobacteria intranasal. The drugs were evaluated at thefollowing doses: RIF, 20 mg/kg; 6f, 6g, 6i, 25 mg/kg for 4 weeks (PO ×OD), bNumber of mice per group, cOne mouse found dead during therapy.

TABLE 4 Comparative antimycobacterial activity data of benzothiazoleconjugates against M. tuberculosis H37Rv (MIC in μg/mL) with closestbenzothiazole compounds. MIC Compound code (μg/mL) 3j 1 6a 1 6f 0.5 6g0.5 6i 0.5 6p 1

1.9

1.4

>6.5

2

2

73

Advantages of Present Disclosure

-   -   1. The present disclosure provides benzothiazole derivatives of        general formula A useful as anti-tubercular chemotherapeutic        agents.    -   2. It also provides a process for the preparation of        benzothiazole derivatives of general formula A.

What is claimed is:
 1. A benzothiazole compound selected from the groupconsisting of formula 3a-p, 4a-h, 6a-t and 8a-d set forth below:

R=H, CH₃, OCH₃, CF₃, OCF₃, F, Cl, NO₂ X=O, S

R=H, CH₃, OCH₃, CF₃, OCF₃, F, Cl, NO₂

Ar=Phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl,4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,2-chloro-3-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,pyridyl, nicotinyl, isonicotinyl, 5-nitro-2-furyl, styryl,4-fluorostyryl, 4-methylstyryl, 4-methoxystyryl, 4-trifluorostyryl,4-trifluoromethoxystyryl

Ar=5-nitro-2-furyl, 1-methyl-4-nitro-1H-2-pyrrolyl,1-methyl-5-nitro-1H-2-imidazolyl, 1-methyl-3-nitro-1H-2-pyrazolyl. 2.The benzothiazole compound as claimed in claim 1 wherein the structuralformula of the representative compounds are: 3a) 5-nitro-2-furaldehyde2-(1,3-benzothiazole-2-yl)hydrazone; 3b) 5-nitro-2-thiophenecarbaldehyde2-(1,3-benzothiazole-2-yl)hydrazone; 3c) 5-nitro-2-furaldehyde2-(6-methyl-1,3-benzothiazole-2-yl)hydrazone; 3d)5-nitro-2-thiophenecarbaldehyde2-(6-methyl-1,3-benzothiazole-2-yl)hydrazone; 3e) 5-nitro-2-furaldehyde2-(6-methoxy-1,3-benzothiazole-2-yl)hydrazone; 3f)5-nitro-2-thiophenecarbaldehyde2-(6-methoxy-1,3-benzothiazole-2-yl)hydrazone; 3g) 5-nitro-2-furaldehyde2-(6-trifluoromethyl-1,3-benzothiazole-2-yl)hydrazone; 3h)5-nitro-2-thiophenecarbaldehyde2-(6-trifluoromethyl-1,3-benzothiazole-2-yl)hydrazone; 3i)5-nitro-2-furaldehyde2-(6-trifluoromethoxy-1,3-benzothiazole-2-yl)hydrazone; 3j)5-nitro-2-thiophenecarbaldehyde2-(6-trifluoromethoxy-1,3-benzothiazole-2-yl)hydrazone; 3k)5-nitro-2-furaldehyde 2-(6-fluoro-1,3-benzothiazole-2-yl)hydrazone; 3l)5-nitro-2-thiophenecarbaldehyde2-(6-fluoro-1,3-benzothiazole-2-yl)hydrazone; 3m) 5-nitro-2-furaldehyde2-(6-chloro-1,3-benzothiazole-2-yl)hydrazone; 3n)5-nitro-2-thiophenecarbaldehyde2-(6-chloro-1,3-benzothiazole-2-yl)hydrazone; 3o) 5-nitro-2-furaldehyde2-(6-nitro-1,3-benzothiazole-2-yl)hydrazone; 3p)5-nitro-2-thiophenecarbaldehyde2-(6-nitro-1,3-benzothiazole-2-yl)hydrazone; 4a)N′2-(1,3-benzothiazol-2-yl)-5-nitro-2-furancarbohydrazide; 4b)N′2-(6-methyl-1,3-benzothiazol-2yl)-5-nitro-2-furancarbohydrazide; 4c)N′2-(6-methoxy-1,3-benzothiazol-2-yl)-5-nitro-2-furancarbohydrazide; 4d)N′2-(6-trifluoromethyl-1,3-benzothiazol-2-yl)-5-nitro-2-furancarbohydrazide;4e)N′2-(6-trifluoromethoxy-1,3-benzothiazol-2-yl)-5-nitro-2-furanecarbohydrazide;4f) N′2-(6-fluoro-1,3-benzothiazol-2-yl)-5-nitro-2-furanecarbohydrazide;4g) N′2-(6-chloro-1,3-benzothiazol-2-yl)-5-nitro-2-furanecarbohydrazide;4h) N′2-(6-nitro-1,3-benzothiazol-2-yl)-5-nitro-2-furanecarbohydrazide;6a) N2-[2-(benzoylamino)-1,3-benzothiazol-6-yl]-5-nitrofuramide; 6b)N2-{2-[(4-methylbenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6c)N2-{2-[(4-methoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6d)N2-{2-[(4-trifluoromethylbenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6e)N2-{2-[(4-trifluoromethoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6f)N2-{2-[(4-fluorobenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6g)N2-{2-[(4-chlorobenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6h)N2-{2-[(2-chloro-3-methoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6i)N2-{2-[(3,5-dimethoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6j)N2-{2-[(3,4,5-trimethoxybenzoyl)amino]-1,3-benzothiazol-6-yl}-5-nitrofuramide;6k)N5-(6-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-2-yl)-1,3-benzodioxole-5-carboxamide;6l)N4-(6-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-2-yl)isonicotinamide;6m)N3-(6-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-2-yl)nicotinamide;6n)N2-(2-{[(E)-3-phenyl-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;6o)N2-(2-{[(E)-3-(4-methylphenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;6p)N2-(2-{[(E)-3-(4-methoxyphenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;6q)N2-(2-{[(E)-3-(4-trifluoromethylphenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;6r)N2-(2-{[(E)-3-(4-trifluoromethoxyphenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;6s)N2-(2-{[(E)-3-(4-fluorophenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl)-5-nitro-2-furamide;6t)N2-(2-{[(E)-3-(4-chlorophenyl)-2-propenoyl]amino}-1,3-benzothiazol-6-yl)-5-nitro-2-furamide;8a)N2-(2-{[(5-nitro-2-furyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-5-nitro-2-furamide;8b)N2-(2-{[(1-methyl-4-nitro-1H-2-pyrrolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-4-nitro-1H-2-pyrrolcarboxamide;8c)N2-(2-{[(1-methyl-5-nitro-1H-2-imidazolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-5-nitro-1H-2-imadazolecarboxamide;or 8d)N2-(2-{[(1-methyl-3-nitro-1H-2-pyrazolyl)carbonyl]amino}-1,3-benzothiazol-6-yl}-1-methyl-3-nitro-1H-2-pyrazolecarboxamide.3. A pharmaceutical composition comprising the compound of claim 1 and apharmaceutically acceptable carrier.